COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
En Liang,1 Xiaojun Li,2 Wenjun Fu,2 Changtong Zhao,1 Baoying Yang,3 Zhonghua Yang2 1Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Centre for Integrative Medicine, School of Basic Medical Science,...
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2021
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| Acceso en línea: | https://doaj.org/article/08c2487132fd4b6da7e0cc5111993e62 |
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| Sumario: | En Liang,1 Xiaojun Li,2 Wenjun Fu,2 Changtong Zhao,1 Baoying Yang,3 Zhonghua Yang2 1Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Neurosurgery, Guangdong Sanjiu Brain Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Baoying YangDepartment of Neurosurgery, Guangdong Sanjiu Brain Hospital, No. 578 Shatai Nan Road, Baiyun District, Guangzhou, 510510, People’s Republic of ChinaEmail yby7899@163.comZhonghua YangCentre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, No. 232 Waihuan Dong Road, Panyun District, Guangzhou, 510006, People’s Republic of ChinaEmail yangzhonghua@gzucm.edu.cnBackground: The suppressor of cytokine signaling 3 (SOCS3) is a specific negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling, which is predominantly activated to induce neuroinflammatory response in microglia and functions essential roles during cerebral ischemia-reperfusion (I/R) injury. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a signaling platform controlling protein stability by remodeling of cullin-RING ubiquitin ligases, which is recently reported to specifically recognize proteins with SOCS-box domains. However, whether SOCS3 is related to COP9 signalosome in neuroinflammation during cerebral I/R injury is completely unclear.Methods: Mice subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion, and BV2 microglia cells treated with oxygen-glucose deprivation and reoxygenation (OGD/R) were used to mimic cerebral I/R injury. Western blot, qRTPCR, immunofluorescence, and co-Immunoprecipitation assays were performed to explore the regulatory mechanism of SOCS3 on neuroinflammation and the relationship of SOCS3 and COP9 signalosome during cerebral I/R injury.Results: SOCS3 expression is significantly upregulated in microglia during OGD/R treatment, and overexpression of SOCS3 suppresses OGD/R-induced STAT3 activation and inflammatory factor expression. Furthermore, we find that COP9 signalosome subunit 3 (CSN3) interacts with SOCS3 protein to enhance its stability, thereby resulting in restricting OGD/R-induced STAT3 activation and inflammatory response. Moreover, we find that knockdown of CSN3 evidently accelerates STAT3 activation, and aggravates cerebral I/R injury in vivo.Conclusion: CSN3 restricts neuroinflammatory responses during cerebral I/R injury through stabilizing SOCS3 protein and indicates that CSN3 a potential therapeutic target for cerebral I/R injury.Keywords: cerebral ischemia-reperfusion injury, neuroinflammation, suppressor of cytokine signaling 3, constitutive photomorphogenesis 9 signalosome, signal transducer and activator of transcription 3 |
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